Significant progress has been made to elucidate the mechanism of lupus autoantibody diversification and to identify important HLA-D restriction elements in response to SLE-related autoantigens. Crossreactive autoantibodies and the expansion of antigen-specific T cells reactive to one or more SLE-related autoantigens are important in the diversification of autoantibody response. With current available transgenic mice expressing D region molecules, DR2 and DR3 are the dominant determinants controlling the magnitude of the precipitating antibody response to recombinant Ro60, and for intermolecular epitope spreading to Ro52. With SmD as the immunogen, DR3 and DQ6 (DQ6B1*0602) were shown to be dominant in the generation of specific anti-SmD antibodies. In DR3 transgenic mice, intermolecular B epitope spreading to A-RNP, C-RNP, and SmB was found. In the case of the DQ6 transgenics, specific antibodies to A-RNP and SmB were detected. In addition, a new model of lupus prone mice, NZM2328 has been characterized and two unique congenic lines have been generated. The NZM2328 and its congenic lines will be useful in the proposed experiments. Based on these findings, this application is to explore the role of HLA-D region and T epitopes in SLE related autoantigens in the pathogenesis of SLE. Four specific aims are proposed. Specific Aim 1: To determine the role of HLA-D molecules in the pathogenesis of SLE. Specific Aim 2: To complete the mapping of T and B epitopes of the selected SLE related antigen SmD and to determine the mechanism of autoantibody diversification. Specific Aim 3: To determine the structural requirement for peptides from SLE related autoantigens. Specific Aim 4: To determine whether T cells reactive to DR restricted peptides mapped in specific aim 2 are present in patients with lupus and in normal controls. This proposal will provide significant information regarding the role of T cell receptor degeneracy, T cell epitopes and molecular mimicry in the induction of autoimmunity in SLE. The proposed experiments will provide new information regarding autoantibody diversification and may also provide data or clues regarding the nature of the initiating antigens. In addition, experiments are proposed to test directly whether HLA-D genes can directly support the development of SLE. The understanding of the role of HLA- D region in the pathogenesis of SLE and the initiation events is crucial in our approach for the prevention and therapy of this disorder.